Post-Remission, Skip Stem Cell Transplant?

Patients with mantle cell lymphoma (MCL) who show undetectable minimal residual disease (MRD) after initial treatment with chemotherapy show no significant overall or progression-free survival benefit from subsequent stem cell transplantation compared with those receiving maintenance therapy alone, new research shows.

“[These findings] could be practice-changing, because over 70% of patients in the study were MRD-negative [after chemotherapy],” said first author Timothy S. Fenske, MD, of the Medical College of Wisconsin, Milwaukee, Wisconsin, at a press briefing on the study at the American Society of Hematology (ASH) 66th Annual Meeting and Exposition in San Diego earlier this month. 

“Historically, somewhere in the range of 1% to 2% of patients actually die from complications of stem cell transplantation, while other patients will experience significant toxicities and effects on their quality of life, so if we can safely spare those patients the potential toxicities of transplant, that would be a big step forward.”

MCL, a B-cell, non-Hodgkin lymphoma, commonly affects older patients, and while autologous hematopoietic cell transplantation (auto-HCT) has been recommended for patients who achieve a complete response following front-line chemotherapy, the practice has become controversial in recent years with the advent of effective induction and maintenance regimens, including those containing high-dose cytarabine, rituximab, and BTK inhibitors. 

To investigate whether patients who are found to have a deep first remission based on MRD after an initial line of treatment can be safely spared auto-HCT, Fenske and colleagues conducted the EA4151 trial, involving 650 patients with MCL enrolled between August 2017 and July 2024 who achieved a first complete remission.

Patients who achieved MRD negativity, as assessed by clonoSEQ, a high-throughput MRD assay, were randomly assigned 1:1 to treatment either with auto-HCT plus 3 years of maintenance rituximab (n = 257) or to 3 years of maintenance rituximab alone (n = 259).

Those who were found to be MRD-positive or indeterminate after front-line treatment were further randomly assigned to two additional groups, each receiving auto-HCT plus 3 years of maintenance rituximab (n = 49 and n = 85, respectively).

The patients had a median age of 60 (range, 27-70), and 73% received intensive induction therapy, defined as high-dose cytarabine‒containing, while the remaining 27% had nonintensive induction.

Additional treatment with a BTK inhibitor was given to 7.2% of patients during induction and to 0.3% during maintenance.

With a median follow-up of 2.7 years at the interim analysis, there were no significant differences in the estimated overall survival among those who did and did not receive auto-HCT among all randomized patients (hazard ratio [HR], 1.11; P = .66). 

As some patients assigned to auto-HCT opted not to receive the treatment upon learning that they were MRD-negative, the authors also assessed only those who were treated as assigned and again found no significant survival difference between those who did and did not receive auto-HCT (HR, 1.00; P = .99).

Further results also showed no significant differences between the two groups in terms of 3-year overall survival (82.1% vs 82.7% for all randomly assigned and 86.2% and 84.8% of those treated as assigned).

On the basis of the results, the trial was stopped early, after the interim analysis.

Other outcomes of estimated progression-free survival rates were not significantly different between those randomly assigned to auto-HCT or no auto-HCT (76.6% and 77.4%), including among those treated as assigned (81.5% vs 80.4%), and the 3-year progression-free survival rates were also similar.

There were no significant differences between the auto-HCT and no-auto-HCT groups randomly assigned, based on patients’ MIPI-c levels (a prognostic index for MCL) or on the intensity of their induction therapy to achieve their first remission.

The overall and progression-free survival rates were also similar among participants who were MRD-positive or MRD-indeterminate and were randomly assigned to receive auto-HCT.

While previous studies have also suggested no benefit of auto-HCT when more recent induction and maintenance regimens were used, Fenske noted that the current study differs from those by having no restrictions on the induction therapy regimen used to achieve the first remission, making the results more generalizable in varying settings.

“We allowed any rituximab-containing induction regimen, including those that incorporated BTK inhibitors, as a reflection of the heterogeneity of treatment that is offered for these patients in the in the United States, in particular,” he said. 

Fenske noted the recent TRIANGLE study, which calls into question the benefit of auto-HCT to an ibrutinib-containing standard treatment in younger patients with MCL.

“Based on our data and on the recently published TRIANGLE study from Europe, we now have two studies that suggest that we can safely omit stem cell transplant in the majority of patients,” Fenske said. 

Of note, “I think identifying MRD-positive patients is also important, since it does appear that those patients may still benefit from transplants,” Fenske said. 

“So, in my practice, I would do this testing in order to differentiate these two populations.”

Commenting on the study in the press briefing, Laurie H. Sehn, MD, MPH, a clinical professor with the British Columbia Cancer Centre for Lymphoid Cancer and the University of British Columbia in Vancouver, Canada, underscored the importance of the study in providing data from a large, randomized cohort. 

“There has been a paucity of trials conducted in a randomized setting [in which MRD] is used in allocating different treatments, so I think this study is really where many areas of the field should be going,” she said. 

“It’s a proof of concept that MRD can be a very valuable tool to allow us to direct tailored approaches to patients and certainly allow us to spare toxicity that we’re currently doing with some of our approaches.” 

“I think this is an evolving area, but this trial is a very good example that we need to start building this into our practice and our clinical trials.”

Mikkael Sekeres, MD, professor of medicine and chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center and University of Miami Miller School of Medicine, in Miami, Florida, who moderated the session, agreed that the study underscores the growing importance of MRD more broadly across blood cancers.

“A lot of different blood cancers have shown that if a patient is MRD-positive, if there’s measurable residual disease at a low level following treatment, that person is more likely to have a relapse of his or her cancer,” he said. “[The current study] shows that if a patient doesn’t have detectable cancer, we can avoid some future treatments.”

However, “what we still have to show is that intervening early when someone is MRD-positive actually affects overall survival,” Sekeres added. “If we intervene at the time of MRD positivity, is somebody living longer than if we waited for a frank morphologic or radiologic relapse?

“We don’t know that yet for the majority of cancers, and that’s really where we need to have these trials focused.”

Fenske reports ties with Bayer, AstraZeneca, BeiGene, Kite, SeaGen, AbbVie, Adaptive Biotechnologies, ADC Therapeutics, Janssen, Lilly, and Ono Pharmaceuticals. Sehn discloses relationships with AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb/Celgene, Genmab, Kite/Gilead, Incyte, Janssen, and Merck. Sekeres reports ties with Kurome, Schrödinger, and Bristol Myers Squibb.